DESCRIPTION: Temporomandibular joint pain is two to three times more common in women than in men, and symptoms are often associated with natural changes in levels of ovarian steroids. Preliminary experiments have demonstrated that galanin, neuropeptide Y and tryptophan hydroxylase are regulated by ovarian steroids in trigeminal ganglia. The overall hypothesis of this application is that ovarian steroids regulate the phenotype of trigeminal neurons by acting upon estrogen receptors during the natural estrous cycle, following ovariectomy and during pregnancy. We will examine 3 stages of the natural cycle, proestrus, when estrogen levels are highest, estrus, when estrogen levels are falling, and diestrus, when estrogen levels are low. We will study pregnant mice, when estrogen levels are stable and high, and ovariectomy, when estrogen levels are stable and low. We will use hormone replacement to determine if the changes are due to estrogen. Responses of the estrogen receptor in regulating gene expression during the natural estrous cycle will be assessed in a transgenic mouse that expresses a luciferase reporter gene under the control of activated estrogen receptors (ERE-luc mice). In Specific Aim 1, we will determine whether trigeminal neurons innervating the TMJ express estrogen receptors, and whether trigeminal neurons increase expression of genes with estrogen response elements in phase with the natural estrous cycle. In Specific Aim 2, we will determine whether the cyclical hormonal changes of the natural estrous cycle and the constant high levels during pregnancy or low levels following ovariectomy alter expression of trigeminal genes involved in nociception and inflammation. In Specific Aim 3, we will examine the effects of ovarian steroids on TMJ and trigeminal responses to TMJ inflammation. These experiments will provide an innovative approach to the mechanism of hormonal regulation of facial pain. [unreadable] [unreadable]